title: Toll-like receptor 3 is required for development of retinopathy caused by impaired all-trans-retinal clearance in mice.
abstract: Chronic inflammation is an important component that contributes to many age-related neurodegenerative diseases, including macular degeneration. Here, we report a role for toll-like receptor 3 (TLR3) in cone-rod dystrophy (CORD) of mice lacking ATP-binding cassette transporter 4 (ABCA4) and retinol dehydrogenase 8 (RDH8), proteins critical for all-trans-retinal clearance in the retina. Increased expression of toll-like receptor-signaling elements and inflammatory changes were observed in Rdh8(-/-)Abca4(-/-) eyes by RNA expression analysis. Unlike 3-month-old Rdh8(-/-)Abca4(-/-) mice that developed CORD, 6-month-old Tlr3(-/-)Rdh8(-/-)Abca4(-/-) mice did not evidence an abnormal retinal phenotype. Light-induced retinal degeneration in Tlr3(-/-)Rdh8(-/-)Abca4(-/-) mice was milder than that in Rdh8(-/-)Abca4(-/-) mice, and a 2-fold increased TLR3 expression was detected in light-illuminated retinas of Rdh8(-/-)Abca4(-/-) mice compared with nonilluminated retinas. Poly(I-C), a TLR3 ligand, caused caspase-8-independent cellular apoptosis. Whereas poly(I-C) induced retinal cell death in Rdh8(-/-)Abca4(-/-) and WT mice both in vivo and ex vivo, this was not seen in mice lacking Tlr3. Far fewer invasive macrophage/microglial cells in the subretinal space and weaker activation of Muller glial cells were exhibited by Tlr3(-/-)Rdh8(-/-) Abca4(-/-) mice compared with Rdh8(-/-)Abca4(-/-) mice at 3 and 6 months of age, indicating that loss of TLR3 inhibits local inflammation in the retina. Both poly(I-C) and endogenous products emanating from dying/dead retinal cells induced NF-κB and IRF3 activation. These findings demonstrate that endogenous products from degenerating retina stimulate TLR3 that causes cellular apoptosis and retinal inflammation and that loss of TLR3 protects mice from CORD.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Satomi
authors.initials: S
authors.lastname: Shiose
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Okano
authors.forename: Sanhita
authors.initials: S
authors.lastname: Roy
authors.forename: Hideo
authors.initials: H
authors.lastname: Kohno
authors.forename: Johnny
authors.initials: J
authors.lastname: Tang
authors.forename: Eric
authors.initials: E
authors.lastname: Pearlman
authors.forename: Tadao
authors.initials: T
authors.lastname: Maeda
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D020869:Gene Expression Profiling; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D012162:Retinal Degeneration / Q000209:etiology*; D012164:Retinal Diseases / Q000209:etiology*; D012172:Retinaldehyde / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000502:physiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D012172:Retinaldehyde; D051196:Toll-Like Receptor 3; C512841:Abca4 protein, mouse; C519703:TLR3 protein, mouse; C525880:HSD17B6 protein, mouse